It has been recognized for some time that the transmission of signals through the nervous system is mediated by a variety of neurotransmitters, each of which has a complementary receptor in the neuron. A substantial number of classes of neurotransmitters and their receptors have been recognized.
One important excitatory neurotransmitter is the amino acid L-glutamate. Receptors which respond to this amino acid have been divided into NMDA and non-NMDA receptors; NMDA, N-methyl-D-aspartate, is an additional neurotransmitter which has its own class of receptors. NMDA receptors are known to be regulated by a glycine binding site which regulates the ability of the neuron to respond to NMDA; glycine in nanomolar concentrations potentiates the NMDA receptor-induced current in a strychnine insensitive manner. Substances which behave as agonists or antagonists with respect to NMDA receptors can therefore interact either with the receptor site for NMDA or the receptor site for glycine or both. Antagonists for these NMDA receptors ameliorate the effects of L-glutamine and are therefore beneficial in the treatment of degenerative neural diseases which are characterized by abnormal neuronal stimulation, such as epilepsy, brain degeneration due to stroke or heart attack, Alzheimer's disease, Lou Gehrig's's disease, and Huntington's disease.
The compound 6-cyano-7-nitroquinoxaline 2,3-dione (CNQX) and the related compound 6,7-dinitro-quinoxaline-2,3-dione (DNQX) are known to depress the excitation of spinal cord neurons which are induced by the stimulation of non-NMDA receptors. See U.S. Pat. No. 4,812,458. However, it was also reported that these compounds had little or no effect on responses produced by NMDA (Honore, T. S. et al., Science (1986) 241:701-703; Blake, J. F. et al., Neuro Sci Let (1988) 89:182-186; Fletcher, E. J., Brit J Pharmacol (1988) 586-587; Dryer, J. et al., Neuro Sci Let (1988) 87:104-108).
Although others have shown that CNQX and DNQX do not interfere with the action of NMDA itself, it has been shown that DNQX produces a shift to the right in the NMDA concentration response curve and a decrease in maximal response at high antagonist concentrations (Birch, P. J. et al, Eur J Pharmacol (1988) 151:313-315. A similar result was noted when DNQX was replaced in these assays by compounds known to displace labeled glycine from the strychnine insensitive binding site (Kemp, J. A. et al., Proc Natl Acad Sci USA (1988) 85:6347-6350; Kestler, M. et al., Soc Neuro Sci Abst (1987) 13:760. As stated above, it is known that binding glycine to a regulatory site potentiates the response of these receptors to NMDA.
It has now been found that despite its apparent inability to interfere with NMDA stimulation, CNQX, DNQX and their analogs behave as antagonists with respect to stimulation to the NMDA receptor.